Intravesical BCG therapy is effective treatment for non-muscle invasive bladder cancer, however, BCG failure and side effect through live bacterial infection are remaining. In this study, the model of BCG failure were developed by continuous co-culture of tumor cell lines with live BCG. The change of BCG strain (e.g. Tokyo 172 strain to Connaught strain) was effective against BCG resistant cells, however, cells became double resistant shortly. Nanoparticle BCG was effective against BCG double resistant cells. These results suggested that the sequential therapy, the change of BCG strain, and then nanoparticle BCG, might be effective in clinical setting.